The human serotonin transporter protein SERT is the primary target for antidepressants used by a significant fraction of the population and also is a direct target for several drugs of abuse, yet modes of action are still unclear. This proposal utilizes the genetically tractable model organism, Drosophila melanogaster, to study the behavioral roles of serotonin in Drosophila, primarily via genetic manipulation of the serotonin transporter, dSERT. We take advantage of the unique genetic, behavioral and anatomical tools available in this simple yet relevant model. The proposal is based on the finding that very mild alleles of dSERT show striking abnormalities in circadian behaviors. There are four aims: In the first aim, additional and more severe dSERT alleles will be generated and characterized, and dSERT overexpression and directed under-expression will be studied. In the second aim, the interactions of the dSERT with the circadian gene pathways will be studied. In the third aim, new drivers expressing in subsets of serotonergic neurons will be generated that will elucidate brain regions specific for the various behavioral effects of serotonin. The fourth aim will take advantage of information learned in the previous aims to design forward genetic screens for new genes in the serotonergic and dopaminergic pathways. PUBLIC HEALTH RELEVANCE: The serotonin transporter is the primary target of widely prescribed antidepressants, yet much remains to be discovered regarding the function of the neurotransmitter serotonin and its role in human well-being. The fruit fly, Drosophila melanogaster, contains a highly conserved serotonin system and is an important behavioral model with demonstrated relevance for higher vertebrates. This proposal uses the fruit fly to better understand the behavioral biology of serotonin.